Dibenzocycloheptenes substituted

ABSTRACT

The invention relates to new dibenzo (a,d) cycloheptenes of the formula:   WHEREIN Y, Y&#39;&#39; and Y&#39;&#39;&#39;&#39; are selected from the group consisting of hydrogen, halogen, lower alkyl substituted lower alkyl, lower alkoxy and trifluoromethyl; R which may attached in 5-, 10- or 11- position represents a radical of the formula:   wherein R1 is hydrogen, substituted lower alkyl or lower alkyl, R2 is hydrogen, lower alkyl substituted lower alkyl or lower alkenyl, R3 is lower alkyl substituted lower alkyl, lower alkenyl, lower alkynyl or aralkyl, OR, R2 and R3 together represent the alkylene moiety of a nitrogenous heterocycle, AND SALTS THEREOF WITH AN ACID. They have therapeutical uses.

United States Patent [19] Vincent et al.

[ Sept. 16, 1975 DIBENZOCYCLOHEPTENES SUBSTITUTED [75] Inventors: Michel Vincent, Bagneux; Georges Remond, Versailles; Michel Laubie, Vaucresson, all of France [73] Assignee: Science Union et Cie, Society Francaise de Recherche Medicale, Suresnes, France [22] Filed: Jan. 24, 1973 [21] Appl. No.: 326,362

[30] Foreign Application Priority Data Jan. 24, 1972 United Kingdom 3237/72 [52] US. CL... 260/558 R; 260/239 B; 260/239 BC; 260/243 B; 260/247.2 A; 260/268 T;

F; 260/326 A; 260/326.33; 260/558 P;

[51] Int. Cl. C07C 103/78 [58] Field of Search 260/558, 559

[56] References Cited UNITED STATES PATENTS 3,287,409 ll/l966 Leonard et a1. 260/558 3,726.870 4/1973 Rey-Bellct et al. 260/558 Primary ExaminerHarry l. Moatz Attorney, Agent, or Firm-()mri M. Behr [57] ABSTRACT The invention relates to new dibenzo (a,d) cycloheptenes of the formula:

wherein Y, Y and Y are selected from the group consisting of hydrogen, halogen, lower alkyl substituted lower alkyl, lower alkoxy and trifluoromethyl;

R which may attached in 5-, 10- or l1 position represents a radical of the formula:

They have therapeutical uses.

14 Claims, No Drawings DlBENZOCYCLOI-[EPIENES SUBSTITUTED This invention relates to new substituted 1,3-diamino 2-propanols and to a process for their preparation.

The present invention provides a new substituted 1,3- diamino 2-propanols of the general formula (I):

Wherein Y, Y and Y" which may be the same or different, each represent a hydrogen atom, a halogen atom, a lower alkyl radical, substituted lower alkyl radical, a lower alkoxy radical or a trifluoromethyl group.

R which may be attached in or ll-position represents a radical of the general formula (II):

wherein R represents a hydrogen atom, a lower alkyl or substituted lower alkyl radical,

R represents a hydrogen atom, a lower alkyl radical, substituted lower alkyl radical, a lower alkenyl radical or benzyl,

R represents a lower alkyl radical, substituted lower alkyl radical, a lower alkenyl radical, a lower alkynyl, or an aryl lower alkyl radical,

or, R and R may be joined together to form with the nitrogen atom to which they are attached a nitrogenous heterocycle having from 5 to 7 links and which may include another hetero atom,

and the dotted line inidcates the eventual presence of a double bond.

The present invention provides also the acid addition salt thereof with a mineral or organic acid.

As far as the invention is concerned, the term lower alkyl is intended to designate a hydrocarbyl residue .having from 1 to 6 carbon atoms in straight or branched chain; The substituents on the substituted lower alkyl radical may be hydroxy, a lower alkoxy or a dilower alkyl amino group. Examples of such lower alkyl are methyl, ethyl, iso propyl, sec butyl, neo penty], ter butyl or n-hexyl.

The term halogen designates preferably fluorine or chlorine. It may be also bromine or iodine.

The term lower alkenyl designates a hydrocarbyl residue with one or several double bonds having from The term aryl lower alkyl designates a phenyl -or a I substituted phenyl-bearing a hydrocarbyl residue having from 1 to 4 carbon atoms. The hydrocarbyl residue may be straight or branched chain. The phenyl ring may carry substituent or substituents such as methoxy, trifluoromethyl, chloro. Examples of such aryl (lower alkyl) radicals are 3,4-dimethoxy benzyl, benzyl, mtrifluoromethyl benzyl, oz-methyl benzyl, pchlorobenzyl, phenylethyl, phenyl propyl or B-methyl phenylethyl.

The term lower alkynyl designates a hydrocarbon residue having a triple bond, having from 2 to 6 carbon atoms such as ethynyl, propyn-l yl, propyn-2 yl or methyl-1 butyn-2 yl. v

The nitrogenous heterocycle may be pyrrolidine, piperidine or hexamethylene imine. It may also include another heteroatom such as a nitrogen atom, a sulfur atom or an oxygen atom. Examples of such heterocycles are oxazolidine, morpholine, thiazolidine, thiamorpholine, piperazine, or homo morpholine. These heterocycles may carry also one or several alkyl residues.

The compounds of the present invention are endowed with interesting pharmacological properties, namely in the cardio-vascular field.

They possess anti-arythmic, cardio depressive, vasodilatatory ant anti-hypertensive properties. They possess little or not any beta-blocker property.

They found a therapeutic use as a drug for the car diac rythm, especially in the treatment of arythmias, tachycardias, angor pectoris and infarctus.

The invention relates also to pharmaceutical compositions comprising as active ingredient one or more compounds of general formula (I) together with an inert non-toxic pharmaceutical carrier.

The pharmaceutical compositions are those suitable for administration by oral, parenteral, sublingual 0r rectal way, for example ampuls, phials, multidoses flasks, tablets, coated tablets, granules, gelules, capsules, sublingual tablets, drinkable solutions or emulsions and suppositories.

They are prepared by known methods.

The dosages may vary broadly depending of the age of the patient, the therapeutic uses and the way of administration. By the adult they vary from 25 mg to mg per unit dosage, especially by intraveinous way, once to five times a day.

The pharmaceutical compositions may include also another active ingredient having similar or synergistic properties, as for example a B-blocker such propanol or practolol, a coronaro-dilatator such as dipyridamol or a nitrated polyol, and an coagulant agent such as Ethylbiscoumacetate or Acenocoumarol or a digitalin-lik'e compound.

The present invention provides also a process for prepan'ng a compound of general formula (I) which consists in reacting a compound of general formula (III):

(III) wherein Y, Y and Y" have the above-given meanings and COR is attached in the 5-, 10-, or 1 1- position. R represents a halogen atom other than fluorine, an hydroxy, an alcoxy radical having from 1 to 5 carbon atoms or a residue,

wherein R" represent a halogen, other than fluorine, a lower alkyl having 1 to carbon atoms or the residue wherein the definition of the substituents Y, Y, and Y" remains unaltered with a diamino propanol of the general formula (IV):

wherein the definitions of R R and R are those previously stated to obtain a compound of general formula wherein the definitions of the substituents R R R Y, Y, Y" are those previously stated which may be, if desired, salified by addition of a mineral or organic acid or when R is benzyl, debenzylated by hydrogenolysis or hydrolysis in acidic medium to obtain a compound having the formula (V):

wherein the substituents Y, Y, Y", R and R are defined as above andthen, if desired, salified the latter by addition of an organicor mineral acid,

or, maybe resolved into its optical isomers by means of a chemical bond with an optically active reagent.

This synthesis may also be effected starting with a resolved diaminopropanol of general formula (IV). By this way the synthesis give directly a compound of general formula (I) under an optically active form.

The production of salts of the compounds of general formula (I) may be carried out by contacting the base with a mineral acid such as hydrochloric, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, or with an organic acid such as acetic acid, propionic acid, lauric acid, benzoic acid, salicylic acid, cinnamic acid, lactic acid, maleic acid, fumaric acid, pyruvic acid, glutarnic acid, oxalic acid, methan sulphonic acid, glucose-l-phosphoric acid, pamoic acid.

The synthesis of compounds of general formula (I) may also be effected in the following manner:

The functionnal derivative of the dibenzocyclo heptene carboxylic acid of general formula (II) is preferably the chloride;

The condensation is effected in an inert organic medium such as an oxygenated solvent or an aromatic hydrocarbon;

I The hydrogenolysis of compound of formula (I), when R is benzyl, is effected by means of hydrogen in the presence of a catalysator belonging to the family of platinum, such as palladium or platinum.

The invention includes also as intermediates compounds:

a. the substituted phthalimides of general formula co B which may be racemic or under is resolved form,

wherein A means a tri (lower alkenyl)-lower alkyl radical, benzyl or B-methyl phenyl ethyl radical B means methyl, benzyl or hydrogen or A and B together with the introgen atom to which they are attached, form a morpholino 0r piperidino radical;

b. the l,3- diamino propanols-2 having the general formula (IV):

under racemic or optically active form, wherein R represents hydrogen or a methyl radical,

D represents an allyl radical, a ter butyl radical, a tri (lower alkenyl) alkyl radical, benzyl or a B-methyl phenyl ethyl radical,

E represents a hydrogen atom, a methyl, a benzyl or an allyl radical,

or, D and E together form with the nitrogen atom to which they are fixed a morpholino 0r piperidino radical.

The starting materials, the (dibenzocycloheptadien 5-) carboxylic acids may be conveniently obtained according to the process described in US. Pat. No. 3,459,859 or preferably when substituted on the phenyl ring or rings according to the process of DAVIS (J. Med. Chem. 7 (1964) 88) or C. VAN DER STELT (J. Med. Chem. 4 (1961) 335).

The starting materials, the (dibenzocycloheptadien- 10) or (dibenzocycloheptadien-l l) carboxylic acids may be conviently obtained according to the process described by PROCIOR (J. Chem. Soc. 1969 (c) 1000) starting from the suitable dibenzocycloheptadien ll-one.

The starting materials, the (dibenzocycloheptatrien- 10) or (dibenzocycloheptatrien-l1) carboxylic acids may be obtained according to the process described by WALKER (J. Org. Chem. 36 (1971) 466).

The 1,3-diamino propanols-2 of general formula (IV) are all the most new compounds.

They may be conveniently obtained by hydrolysing a substituted phthalirnide of the formula:

co R2 /N-CH2 CHOH cu N\ vn co R,

Wherein R and R are defined as above,

by means of a mineral acid according to the procedure described by D. J. Triggle and B. Belleau Canad. J. of Chem. 40 (1962) 1215;

by means of hydrazine according to the procedure described by B. R. Baker J. of Am. Chem. Soc. 77 (1955) 5908;

by means of phenylhydrazine according to the procedure described by Boissonas Nature 169 (1952) 154;

by means of methyl hydrazine or 2,5-dichlorophenylhydrazine according to the procedure described by A. F. Rosenthal J. Org. Chem. 22 (1957) 89,

to obtain a 1,3-diamino propanol-Z of general formula (IV) wherein R, is hydrogen and R and R are defined as above,

or by opening the oxirane ring of a 1,2-epoxy 3- amino propane of formula (VIII) CH2CHCH2N wherein R and R are defined as above,

with ammonia or a primary lower alkylamine,

to obtain a compound of general formula IV wherein R is hydrogen or a lower alkyl radical using a procedure similar to that described by E. A. Steck J. of AM. Chem. Soc. 70 (1948) 4063.

The starting 1,2-epoxy 3-diamino propanes of general formula VIII are obtained in a process similar to that described by Steck by condensing the appropriate amine R and R being defined as above, with epichlorhydrin.

The starting substituted phthalimides of formula (VII) are prepared by condensing N-(2,3-epoxy propyl) phthalirnide with an amine having the formula:

(wherein R and R are defined as above) in an inert solvent and recovering said substituted phthalirnide. The following examples explain the invention without restricting it. The temperatures indicated thereafter are expressed in degrees Centigrade.

EXAMPLE 1 l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-(N-benzyl N-isopropyl amino) 2-propanol and its hydrochloride 13,3 g of l-amino 3-(N-benzyl N-isopropyl amino) Z-propanol, obtained according to the process described by E. A. STECK (J. of Am. Chem. Soc. (1948) 4063) are added to a solution of 15,1 g of (dibenzo (a,d) 1,4-cycloheptadienyl -5) carbonyl chloride in 45 ml ethylether while cooling to 10. Then, the reaction mixture is kept at room temperature under stirring during 12 hours.

The hydrochloride of l-[dibenzo (a,d) 1,4-cycloheptadienyl-S carboxamido] 3-(N-benzyl N- isopropylamino) Z-propanol precipitates and is isolated by sucction, then washed twice with ethylether and dried under vacuum. 20,1 g of the hydrochloride are thus recovered under the form of crystals melting with decomposition at C.

EXAMPLE 2 l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-(N-benzyl N-terbutyl amino) 2propanol and its hydrochloride Using the same procedure as described in example 1 and starting from 16.1 g of (dibenzo (a,d) 1,4-cycloheptadienyl-5) carbonyl chloride and 14.9 g of l-amino 3-(N-benzyl N-terbutylamino) 2-propanol, l-[dibenzo (a,d) 1,4-cycloheptadienyl S-carboxamido] 3-(N-benzyl N-terbutylamino) is obtained with a yield of 71 The free base is then coverted into its hydrochloric acid addition salt which melts at 2l8220.

EXAMPLE 3 l-[dibenzo (a,d) cycloheptatrienyl [5H] S-carboxamido] 3-(morpholino-4) 2-propanol and its hydrochloride Using the procedure of example 1, starting from (dibenzo (a,d) cycloheptatrienyl [5H1-5) carbonyl chloride and from 3-morpholino l-amino Z-propanol. l-[dibenzo (a,d) cycloheptatrientyl-S [5H] carboxamido] 3-(morpholino-4) Z-propanol is obtained as crystals melting at Its hydrochloride is formed by dissolving 0.387 g of the base in 10 ml hydrochloric acid 0.1 N and distillating off the water under reduced pressure.

The starting material 3-morpholino l-amino 2- propanol, new compound, is obtained in the following fashion:

a. condensing N-(2,3'epoxypropy1) phtalimide with morpholine,

b. hydrazinolysing the N-(3-morpholino 2- hydroxypropyl) phtalimide thus obtained in 3- morpholino 1 -arnino 2-propanol I (B.P. 114-118/0.2mrn Hg).

EXAMPLE 4 l-[dibenzo (a,d) 1,4-cycloheptadieny1-5 carboxamido] 3-(morpholino-4) 2-propanol and its hydrochloride Using the procedure described in example 1 and starting from (dibenzo (a,d) l,4-cycloheptadienyl-5) carbonyl chloride and from 3-morpholino l-amino 2- propanol l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-(morpholino-4) 2-propanol is obtained which is isolated under the form of its hydrochloride melting at 242 after recrystallization from methanol.

EXAMPLE 5 l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-piperidino -2-propanol and its hydrochloride Using the same procedure as in example 1 and starting from (dibenzo (a,d) l,4-cycloheptadienyl-5) carbonyl chloride and from 3-piperidino l-amino 2- propanol, l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-piperidino 2-propanol is obtained and transformed into its hydrochloride 'melting at 243244 after recrystallization from ethanol.

The starting material l-amino 3-piperidino 2- propanol, new product, is obtained by the following way:

a. condensing N-(2,3-epoxypropyl) phtalimide with piperidine,

b. hydrazinolysing the N-(3-piperidino 2- hydroxypropyl) phtalimide thus obtained into l-arnino 3-piperidino 2-propano1 (B.p. 9294/O.2mm Hg).

EXAMPLE 6 l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-dia1lylamino 2-propanol and its hydrochloride Using the same procedure as in example I and starting from 3-diallylamino l-amino 2-propanol and from [dibenzo (a,d) 1,4-cycloheptadienyl-5] carbonyl chloride, l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-diallylamino 2-propanol is obtained as crystals melting at 9091 after recrystallization from a mixture of hexane and ether.

The free base is then converted into its hydrochloride by dissolving 0.39 g of the base in 10 ml of hydrochloric acid 0,1 N and evaporated to dryness under reduced pressure.

The starting material 3-diallylamino l-amino 2- propanol is obtained by condensing diallylamine with N-(2,3-epoxypropyl) phthalimide and hydrazinolysing the N-(3-diallylamino 2-hydroxypropyl) phthalimide into 3-dia1lylamino l-amino 2-propanol (B.p. 95-98/0.4mm Hg).

EXAMPLE 7 1-[2,3-dimethoxy dibenzo (a,d) 1,4-cycloheptadienyl-5-carboxamido] 3-(N-terbutyl N-benzylamino) 2-propanol and its hydrochloride Using the same prodedure as in example 1 and starting from (2,3-dimethoxy dibenzo (a,d) 1,4-cycloheptadienyl-S) carbonyl chloride (obtained according to. PROCTOR J. Chem. Soc. (c) 1969, 1000) 1-[2,3-:

dimethoxydibenzo (a,d) 1,4-cyclo heptadienyl-S carboxamido] 3-(N-terbutyl N-benzylamino) 2-propano is obtained as crystals melting at 68'70.

Its hydrochloride is formed by reacting 0.51 g of the free base with 10 ml=0f hydrochloric acid 0,1 N and evaporating to dryness.

The starting 3-(N-benzyl N-te'rbutylamino) l-amino 2-propanol is obtained from the corresponding phtalimide using the same procedure as above (B.p. 124-l35/0.01mm Hg, M.p.

EXAMPLE 8 l-[dibenzo (a,d) l,4-cycloheptadienyl-5 N-methyl carboxamido 3-(N-terbuty1 N-benzylamino) 2-propanol and its hydrochloride.

Using the procedure of example 1 and starting from B-(N-terbutyl N-benzyl amino) l-methylamino 2- propanol, l-[dibenzo (a,d) 1,4-cycloheptadienyl-5 N- methyl carboxamido] 3-(N-terbutyl N-benzylamino) 2-propanol is obtained. It occurs as crystals melting at 101-104 after recrystallization from ether.

The hydrochloric acid addition salt is obtained by contacting the free base with a stoechiometric amount of hydrochloric acid 0,1 N and distillating off the water till dryness under reduced pressure.

The starting material 3-(N-terbutyl N-benzylamino) l-methylamino 2-propanol is obtained according .to the following procedure:

condensing epichlorhydrin with N-terbutylN-benzyl amine into 3-( N-terbutyl N-benzylamino) 1,2-epoxy propane (B.p. 105l 10/0.05mm Hg);

reacting said epoxyde with methylamine to obtain 3- (N-terbutyl N-benzylamino) l-methylamino 2- propanol (B.p. 134-l35/0.05mrn Hg).

EXAMPLE 9 l-[dibenzo (a,d) 1,4cycloheptadienyl-5 carboxamido] 3-(triallyl methylamino) 2-propanol and its hydrochloride Using the procedure of example 1 and starting from 3-(triallyl methylamino) -l-amino 2-propanol 1- [dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-triallyl methylamino 2-propanol is obtained. After recrystallization from cyclohexane it melts at 1 18.

The base is converted into its hydrochloride by dissolving 0.44 of the base in 10ml of 0.1 N-hydrochloric acid and evaporating the water under reduced pressure.

The starting material, the 3-(triallylmethylamino) 1- amino 2-propanol is obtained by condensing triallylmethylamine with (2,3-epoxypropyl) phtalimide and hydrazinolysing the 3-(triallylmethylamino) 2- hydroxypropyl phtalimide, (M.p. 163 164 as hydrochloride). I

EXAMPLE l0 1-[dibenzo (a,d) 1,4-cycloheptadienyl-5 carboxamido] 3-(B-methyl phenylethyl amino 2-propanol and its neutral succinate.

Using the procedure of example 1 and starting from 3-(B-methyl phenylethyl) l-amino 2-propanol 1- [dibenzo (a,d) 1,4-cycloheptdienyl-5 carboxamido] 3-(B-methyl phenyl ethylamino) 2-propano1 is obtained.

The base is then coverted into its neutral succinate which melts at 140 after recrystallization from a mixture of ethanol-ether.

The 3-(,8methylphenylethyl) amino l-amino 2- propanol, which is a new product, is produced from N-(2,3-epoxypropyl) phthalimide and B-methyl phenylethylamine. The thus formed [3-(B-methyl phenylethyl)amino 2-hydroxypropyl] phtalimide (M.p.=l 20) is then converted by reaction with hydrazine into 3-(B-methylphenyl ethyl) amino l-amino 2- propanol (B.p. l35/0.05m m Hg).

EXAMPLE l 1 l-[dibenzo (a,d) l,4-cycloheptadienyl5 carboxamino] 3-(N-benzyl N-methyl amino) 2-propanol and its hydrochloride Using the procedure of example 1 and starting from B-(N-benzyl N-methyl amino) l-amino 2-propanol, l- [dibenzo (a,d) 1,4-cycloheptadienyl5 carboxamido] 3-(N-benzyl Nmethyl amino) 2-propanol is obtained as crystals melting at 1 The free base is then converted into its hydrochloride by dissolving the former in hydrochloric acid 0,1 N and distillating off the water under reduced pressure. The 3-(N-benzyl N-methylamino) l-amino 2-propanol (B.p l l5/0.0lmm Hg) is obtained from [3(N-methyl N- benzylamino) 2-hydroxy propyl] phthalimide (M.p. 93-95 by hydrazinolysis.

EXAMPLE l2 l-[3-chloro dibenzo (a,d) l,4-cycloheptadienyl -5 carboxamido] 3-terbutyl amino 2-propanol and its hydrochloride EXAMPLE 13 Using the procedure of example 1 and starting from (dibenzo (a,d) cycloheptatrienyl [5H] -5) carbonyl chloride, l-[dibenzo (a,d) cycloheptatrienyl [5H] 5- carboxamido] 3-terbutylamino 2-propanol is produced, melting at 1l7118 after recrystallization from ethyl ether. Its hydrochloride is obtained by contacting the base iwith the stoichiometric amount of hydrochloric acid and evaporation to dryness.

EXAMPLE 14 l-[dibenzo (a,d) cycloheptatriene [5H] lO-carboxamido] 3-terbutylamino 2-propanol and its neutral succinate Following the procedure of example 1 and starting from [dibenzo (a,d) cycloheptatrienyl [5H] -10] carbonyl chloride, l-[dibenzo (a,d) cycloheptatrienyl [SH] carboxamido -10] 3-terbutylamino 2-propanol is produced.

It is converted into its neutral succinate by addition in stoichiometric amount, of a solution of succinic acid in ethyl other.

This acid addition salt melts at l59160 after recrystallization from propanol.

The starting material, (dibenzo (a,d) cycloheptatrienyl [5H] -l0) carbonyl chloride is obtained according to known methods from (dibenzo (a,d) cycloheptatrienyl) [5H] -l0) carboxylic acid (WALKER J. Org. Chem. 36 (1971) 466).

In a similar fashion starting from(dibenzo (a,d) 1,4- cycloheptadienyl lO-) carbonyl chloride and from 3- (N-terbutyl N-benzylamino) l-amino 2-propanol, l- [dibenzo (a,d) cycloheptadienyl IO-carboxamido] 3- N-terbutyl N-benzylamino) 2-propanol is produced.

EXAL/IPLE 15 l-[dibenzo (a,d) 1,4-cycloheptadienyl S-carboxamido] 3-dibenzylamino propanol Using the procedure of example 1 and starting from 3-dibenzylamino l-amino 2-propanol, l-[dibenzo (a,d) l,4-cycloheptadienyl S-carboxamido] S-dibenzylamino 2-propanol is produced in a quantitative yield.

The starting material 3-dibenzylamino l-amino 2- propanol is obtained from N( 2,3-epoxypropyl) phthalimide and dibenzylamine by the methods already described. The intermediate (3-(dibenzylamino) 2- hydroxy propyl) phthalimide is converted by reacting with hydrazine hydrate into 3-(dibenzylamino) 1- arnino 2-propanol (B.p. l-190/O.lmm Hg).

EXAMPLE l6 l-[dibenzo a,d) l,4-cycloheptadienyl 5-carboxamido] 3-N-isopropylamino 2-propanol and its acid addition salts 12,4 g of l-[dibenzo (a,d) l,4-cycloheptadienyl 5- carboxamido] S-(N-benzyl N-isopropylamino) 2- propanol (hydrochloride) are dissolved in 70 ml ethanol. 4 g of palladised charcoal containing 10 of palladium are added to this solution.

The air is expelled from the vessel by a stream of nitrogen and thereafter hydrogen is bubbled into it at room temperature under a pressure of 50 atm during 6 hours.

The catalyst is then eliminated by filtration. The filtrate is evaporated to dryness under reduced pressure and the dry residue is taken up with 50 ml water. This aqueous solution is rendered weakly acid by addition of N-hydrochloric acid until a pH value of 2. The solution is extracted twice with ethyl ether and the organic washings are discarded. The aqueous phaseis made alkaline by adding sodium carbonate until a pH value of about 10.

The free base precipitates and is separated by sucction and dried. It is purified by dissolving it in 50 ml ether and cooling. The base crystallized by standing. The crystals are separated, washed with cooled ether and dried at room temperature under reduced pressure.

5,1 g of l-[dibenzo (a,d) l,4-cycloheptadienyl 5- carboxamido] 3-isopropyl amino 2-propanol are thus recovered. It melts at 1l9l20.

It may be converted in its hydrochloride (M.P. 123 with decomposition) or into its methane sulphonate (M.P. 95 dec.).

EXAMPLE l7 l-[dibenzo (a,d) 1,4-cycloheptadienyl -carboxamido] 3-terbutylamino-terbutylamino-propan and its hydrochloride Following the procedure of example 16 and starting from 13,8 g of l-[dibenzo (a,d) 1,4-cycloheptadienyl 5-carboxamido] 3-(N-benzyl N-terbutylamino) 2- propanol (hydrochloride), l-[dibenzo (a,d) 1,4- cycloheptadienyl 5-carboxamido] 3-terbutylamino 2- propanol is produced with a yield of about 86 Its hydrochloride is produced by dissolving the base in a stoichiometric amount of hydrochloric acid in ether and evaporating the solvent till dryness. The

hydrochloride melts at 154 (dec.).

EXAMPLE 1 8 l-[dibenzo (a,d) 1,4-cycloheptadienyl lO-carboxamido] 3-terbutylamino 2-propanol and its hydrochloride EXAMPLE 19 Following the procedure of example 16 and starting from l-[dibenzo (a,d) 1,4-cycloheptadienyl 5- carboxamido] 3(N-benzyl N-methylamino) 2- propanol, l-[dibenzo (a,d) 1,4-cycloheptadienyl 5- carboxamido] 3-methylamino 2-propanol is obtained.

Its hydrochloride after recrystallization from acetonitrile melts at about l45150.

EXAMPLE 20 Following the procedure of example 16 and starting from l-[dibenzo (a,d) l,4-cycloheptadienyl 5- carboxamido] 3-dibenzylamino 2-propanol, l-[dibenzo (a,d) 1 ,4-cycloheptadienyl 5-carboxamido] 3- benzylamino 2-propanol is produced and isolated as the hydrochloride melting at 200C.

What we claim is:

l. A dibenzo cycloheptene of the formula wherein:

Y, Y and Y are selected from the group consisting of hydrogen, halogen, lower alkyl, substituted lower alkyl, lower alkoxy and trifluoromethyl; R, attached to the carbon in 5-, 10- or ll-position, represents a l,3-diamino propanol-Z chain having the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl and substituted lower alkyl,

R is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower alkenyl and benzyl,

R is selected from the group consisting of lower alkyl, substituted lower alkyl, lower alkenyl, lower alkynyl, phenyl lower alkyl and mono and di substituted phenyl lower alkyl, wherein the alkyl moieties of acid phenyl alkyl groups possess 1-4 carbon atoms, I

and the dotted line indicates an optional 10-] 1 double bond wherein the lower alkyl moiety is .a branched or straight chain hydrocarbyl moiety of l-6 carbon atoms,

the substituents on the substituted lower alkyl moiety are an hydroxy, a lower alkoxy and a di-lower alkyl amino, wherein said lower alkoxy and lower alkyl moieties contain 16 carbon atoms,

the substituents on said substituted phenyl moiety are methoxy, trifluoromethyl and chloro,

and their acid addition salt with a therapeutically compatible mineral or organic acid. 7

2. A dibenzo cycloheptene of claim 1 of the formula wherein R, represents a 1,3-diamino propanol-2 chain having the formula:

wherein R, Y, Y and Y" are defined as in claim 1.

6. A compound of claim 1 having the formula:

wherein R, Y, Y and Y" are defined as in claim 1.

7. A compound of claim 1 under racemic or optically active form.

8. A compound of claim 2 selected from the group consisting of l-[dibenzo (a,d) 1,4-cycloheptadienyl 5- carboxarnido] 3-terbutylamino 2-propanol and its acidaddition salts.

9. A compound of claim 2 selected from the group consisting of l-[dibenzo (a,d) 1,4-cycloheptadienyl-5- carboxamido] -3-(N-benzyl N-isopropylamino) 2- propanol and its hydrochloride.

10. A compound of claim 2 selected from the group consisting of l-[dibenzo (a,d) 1,4-cycloheptadienyl-5- carboxamido] -3-(N-benzyl N-tertbutylamino) 2- propanol and its hydrochloride.

11. A compound of claim 2 selected from the group consisting of l-[dibenzo (a,d) 1,4-cycloheptadienyl-5- N-methyl carboxamido]-3-(N-terbutyl N- benzylamino) 2-propanol and its hydrochloride.

12. A compound of claim 2 selected from the group consisting of l-[dibenzo (a,d) 1,4-cycloheptadienyl-5- carboxamido]-3-(B-methyl phenylethyl amino 2- propanol and its neutral succinate.

13. A compound of claim 2 selected from the group consisting of l-[dibenzo (a,d) cycloheptatriene [5H] 10-carboxamido]-3-tertbutylamino 2-propanol and its neutral succinate.

14. A compound of claim 2 selected from the group consisting of l-[dibenzo (a,d) 1,4-cycloheptadienyl-5- carboxamido]-3-methylamin0 2-propanol and its acid addition salts. 

1. A DIBENZO CYCLOHEPTENE OF THE FORMULA
 2. A dibenzo cycloheptene of claim 1 of the formula
 3. A compound of claim 2 selected from the group consisting of 1-(dibenzo(a,d)-1,4-cycloheptadienyl 5-carboxamido) 3-(N-triallyl methylamino) 2-propanol and its hydrochloride.
 4. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) 1,4-cycloheptadienyl 5-carboxamido)3-N-isopropylamino 2-propanol and its acid addition salts.
 5. A compound of claim 1, having the formula:
 6. A compound of claim 1 having the formula:
 7. A compound of claim 1 under racemic or optically active form.
 8. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) 1,4-cycloheptadienyl 5-carboxamido) 3-terbutylamino 2-propanol and its acid-addition salts.
 9. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) 1,4-cycloheptadienyl-5-carboxamido) -3-(N-benzyl N-isopropylamino) 2-propanol and its hydrochloride.
 10. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) 1,4-cycloheptadienyl-5-carboxamido) -3-(N-benzyl N-tertbutylamino) 2-propanol and its hydrochloride.
 11. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) 1,4-cycloheptadienyl-5-N-methyl carboxamido)-3-(N-terbutyl N-benzylamino) 2-propanol and its hydrochloride.
 12. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) 1,4-cycloheptadienyl-5-carboxamido)-3-( Beta -methyl phenylethyl amino 2-propanol and its neutral succinate.
 13. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) cycloheptatriene (5H) 10-carboxamido)-3-tertbutylamino 2-propanol and its neutral succinate.
 14. A compound of claim 2 selected from the group consisting of 1-(dibenzo (a,d) 1,4-cycloheptadienyl-5-carboxamido)-3-methylamino 2-propanol and its acid addition salts. 